Dopamine acts upon neurons through two families of dopamine receptors, D1-like receptors (D1Rs) and D2-like receptors (D2Rs). The D2-like receptor family consists of D2, D3 and D4 receptors, with the D2 and D3 receptors being the most homologous pair and sharing extensive sequence identity in the transmembrane domain and in the putative ligand binding site. See Chien, E. Y. T., et al. “Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist”, Science 330:1091-1095 (2010). Pharmacological studies have reported that D1 and D5 receptors (D1/D5), namely D1-like receptors, couple to stimulatory Gs proteins and stimulate adenylyl cyclase (AC) activity and increase cytosolic cyclic adenosine monophosphate (cAMP) levels, whereas D2, D3, and D4 receptors, namely D2-like receptors, couple to inhibitory Gi/o proteins that suppress AC activity and decrease cAMP production.
D3 receptor mRNA has been found in specific regions of the rodent and human brain that have been associated with addiction. See e.g., Micheli, F.; Heidbreder, C. “Selective dopamine D3 receptor antagonists. A decade of progress: 1997-2007”, Expert Opin. Ther. Patents 18(8):821-840 (2008). In the human brain, D3 receptors are expressed primarily in mesolimbic regions such as the ventral striatum, ventral pallidum, internal globus pallidus, nucleus accumbens, islands of Calleja, olfactory tubercle, lateral septum, amygdala and ventral tegmental area (VTA). See e.g., Cho, D. I. et al. “Current perspectives on the selective regulation of dopamine D(2) and D(3) receptors”, Archives of Pharmacol. Research, 33:1521-1538 (2010); Gurevich, E. V., Joyce, J. N. “Distribution of dopamine D3 receptor expressing neurons in the human forebrain: Comparison with D2 receptor expressing neurons.” Neuropsychopharmacology, 20:60-80 (1999); and Searle, G. et al. “Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist.” Biological Psychiatry, 68:392-399 (2010). These brain areas have been found to govern certain motivational behaviors and the reward properties of addictive drugs. See Heidbreder, C. A.; Newman, A. H. “Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders” Ann. N.Y. Acad. Sci. Addiction Reviews 2, 1187:4-34 (2010). In addition, certain D3 receptor gene polymorphisms have been linked to neuropsychiatric disorders. For example, the rs6280 polymorphism which encodes the functional missense mutation Ser9Gly, may enhance reward-related dopamine release and this polymorphism has been associated with nicotine dependence, alcohol dependence and early onset heroin dependence. See Keck, T. M. et al. “Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis” J. Med. Chem. 58:5361-5380 (2015). Based on efficacy observed in various animal models of reinstatement to drug-seeking behavior, antagonism of the D3 receptor would likely reduce relapse to drug-induced, cue-induced and stress-induced consumption post-abstinence as well as provide for pro-cognitive effects. See e.g., Heidbreder, C. “Rationale in support of the use of selective dopamine D3 receptor antagonists for the pharmacotherapeutic management of substance use disorders” Naunyn-Schmiedeberg's Arch. Pharmacol. 386:167-176 (2013); Hachimine, P. et al. “The novel dopamine D3 receptor antagonist, SR 21502, reduces cocaine conditioned place preference in rats” Neuroscience Letters 569:137-141 (2014); and Galaj, E. et al. “The selective dopamine D3 receptor antagonist, SR 21502, reduces cue-induced reinstatement of heroin seeking and heroin conditioned place preference in rats” Drug and Alcohol Dependence 156:228-233 (2015). For example, D3 antagonist compounds may be useful in the treatment of addiction, such as relapse addiction, to drug substances such as the psychostimulants cocaine, amphetamine, methamphetamine and the like; opioids such as heroin, morphine, oxycodone, hydrocodone, hydromorphone and the like; nicotine; cannabinoids, such as marijuana; and alcohol.
Dopamine D3 receptors have also been implicated in numerous other neuropharmacological and neurobiological functions. For example, D3 receptors have been implicated as having a role in different types of memory function, such as cognition. Antagonism of the D3 receptor has been shown to improve cognitive deficits in certain animal models. See e.g., Watson, D. J. G., et al. “Selective Blockade of Dopamine D3 Receptors Enhances while D2 Antagonism Impairs Social Novelty Discrimination and Novel Object Recognition in Rats: A Key Role for the Prefrontal Cortex”, Neuropsychopharmacology 37:770-786 (2012). D3 receptors have also been associated with numerous other diseases and disorders. D3 antagonists may be useful for the treatment of the following diseases or disorders: impulse control disorders such as pathological gambling, hypersexuality, compulsive shopping [See Moore, T. et al. “Reports of Pathological Gambling, Hypersexuality, and Compulsive Shopping Associated with Dopamine Receptor Agonist Drugs”, JAMA Internal Medicine 2014, 174(12), 1930-1933], obsessive control disorders; eating disorders such as anorexia nervosa, activity-based anorexia [See e.g., Klenotich, S. J. et al. “Dopamine D2/3 receptor antagonism reduces activity-based anorexia” Transl. Psychiatry 5:e613 (2015)] or binge eating and obesity [See e.g., Nathan, P. J. et al. “The effects of the dopamine D3 receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects”, International Journal of Neuropsychopharmacology 15:149-161 (2012)]; aggressiveness; tremors; schizophrenia and other psychoses [See e.g., Gross, G. et al. “Dopamine D3 receptor antagonism—still a therapeutic option for the treatment of schizophrenia”, Naunyn-Schmiedeberg's Arch. Pharmacol. 386:155-166 (2013)]; unipolar and bipolar depression; disorders caused by stress such as anxiety and toxicomania; autistic spectrum disorder; attention-deficit hyperactivity disorder (ADHD); restless leg syndrome; pain; nausea (such as nausea caused by cytotoxic agents or dopaminergic agents); Parkinson's disease; premature ejaculation; L-Dopa induced dyskinesia (LID) and Tardive dyskinesia [See e.g. Solis, O. et al. “Dopamine D3 receptor modulates L-DOPA-Induced Dyskinesia by Targeting D1 Receptor Mediated Striatal Signaling”, Cerebral Cortex Oct. 18, 2015, 1-12; Payer, D. et al. “D3 dopamine receptor preferring [11C]PHNO PET imaging in Parkinson patients with dyskinesia” Neurology published ahead of print Dec. 30, 2015; and Mahmoudi, S. et al. “Upregulation of Dopamine D3, Not D2, Receptors Correlates With Tardive Dyskinesia in a Primate Model”, Movement Disorders 2014, 29(9), 1125. Antagonism of the D3 receptor may provide efficacious treatments for these diseases and disorders. In addition, antagonism of peripheral D3 receptors in the kidney may provide a renoprotective effect, for example in patients with diabetes or who have been treated with a metabolism-disrupting antipsychotic agent. See e.g., Micheli, F.; Heidbreder, C. “Dopamine D3 receptor antagonists: A patent review (2007-2012)”, Expert Opin. Ther. Patents 23(3):363-381 (2013).
New or improved agents that modulate (such as antagonize or partially agonize) D3 receptors are needed to provide improved therapeutic options for the treatment of diseases or conditions associated with dysregulated activation of the D3 receptor, such as those described herein. It may also be desirable to devise new agents which exhibit selectivity for the D3 receptor over the closely related D2 receptor. See Keck, T. M. et al. “Beyond Small-Molecule SAR: Using the Dopamine D3 Receptor Crystal Structure to Guide Drug Design” Advances in Pharmacology, 69:267-300 (2014).